[go: up one dir, main page]

US9701661B2 - 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase - Google Patents

2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase Download PDF

Info

Publication number
US9701661B2
US9701661B2 US14/798,307 US201514798307A US9701661B2 US 9701661 B2 US9701661 B2 US 9701661B2 US 201514798307 A US201514798307 A US 201514798307A US 9701661 B2 US9701661 B2 US 9701661B2
Authority
US
United States
Prior art keywords
moieties
substituents
compound
fluoro
independently selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US14/798,307
Other languages
English (en)
Other versions
US20160009690A1 (en
Inventor
Richard B. Silverman
Paramita Mukherjee
Hien M. Nguyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Northwestern University
Original Assignee
Northwestern University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Northwestern University filed Critical Northwestern University
Priority to US14/798,307 priority Critical patent/US9701661B2/en
Assigned to NORTHWESTERN UNIVERSITY reassignment NORTHWESTERN UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MUKHERJEE, Paramita, NGUYEN, HIEN M., SILVERMAN, RICHARD B.
Publication of US20160009690A1 publication Critical patent/US20160009690A1/en
Priority to US15/602,833 priority patent/US9878996B2/en
Application granted granted Critical
Publication of US9701661B2 publication Critical patent/US9701661B2/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • Nitric oxide is a cell signaling molecule that acts as a neurotransmitter in the human brain.
  • various disease states can result. For instance, high levels of NO contribute to the damage of brain tissue, protein aggregation and degradation of the sort associated with various neurodegenerative disease states including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), cerebral palsy and stroke/ischemic brain damage.
  • nNOS neuronal nitric oxide synthase
  • neurodegeneration can be attenuated or prevented.
  • nNOS blood-brain barrier
  • iNOS inducible NOS
  • eNOS endothelial NOS
  • the present invention can be directed to compounds of formula
  • Ar can be selected from optionally-substituted aryl and heteroaryl moieties, where such substituents can be selected from halo, alkyl, haloalkyl, cyano and amino substituents;
  • L 1 can be selected from optionally-substituted divalent C 1 -C 4 alkylene moieties, where such substituents can be selected from halo, alkyl and divalent methylene substituents;
  • R 1 can be selected from H, alkyl and divalent alkylene substituents;
  • L 2 can be selected from optionally-substituted divalent C 1 -C 3 alkylene moieties, where such substituents can be selected from halo, aza (—NH—) and substituted aza (—NR 2 ) moieties, where R 2 can be selected from alkyl and divalent alkylene substituents;
  • aryl and heteroaryl moieties as can be selected from moieties of the sort described, inferred herein or as would otherwise be understood by those skilled in the art and made aware of this invention.
  • Ar can be selected from fluoro-, chloro- and cyano-substituted phenyl moieties, pyridinyl, methyl- and methyl- and amino-substituted pyridinyl moieties.
  • L 1 can be selected from (CH 2 ) n moieties, where n can be an integer selected from 1-3, CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 can be independently selected from H, fluoro, and alkyl substituents and moieties where R 4 and R 5 can together and R 5 and R 6 can together form methylene substituents and cyclopropyl moieties.
  • L 2 can be selected from (CH 2 ) m , CH(R 7 )CH(R 8 ), (CH 2 ) m NH and (CH 2 ) m NR 2 moieties, where m can be an integer selected from 1-3 and each of R 7 -R 8 can be independently selected from H and fluoro substituents, and moieties where R 1 and R 2 can together form a divalent C 1 -C 2 alkylene substituent and a diazacycloalkyl moiety.
  • L 2 can be positioned alternatively about the phenyl, pyrimidinyl or pyridinyl moiety shown.
  • E 1 -E 3 can be N.
  • E 1 and E 3 can be N
  • E 5 can be N.
  • Ar can be selected from fluoro-, chloro- and cyano-substituted phenyl moieties.
  • L 1 can be selected from (CH 2 ) n moieties, where n can be an integer selected from 1-3, and CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 can be independently selected from H and fluoro substituents.
  • L 2 can be selected from (CH 2 ) m and CH(R 7 )CH(R 8 ), moieties, where m can be an integer selected from 1-3 and each of R 7 -R 8 can be independently selected from H and fluoro substituents.
  • the present invention can also be directed to compounds of a formula
  • Ar, L 1 , L 2 and E 4 -E 7 can independently be selected from moieties of the sort discussed above or illustrated elsewhere herein, and salts thereof.
  • Ar can be selected from fluoro-, chloro- and cyano-substituted phenyl moieties, pyridinyl, methyl- and methyl- and amino-substituted pyridinyl moieties;
  • L 1 can be selected from optionally substituted divalent C 1 -C 4 alkylene moieties, where such substituents can be selected from halo, alkyl and divalent methylene substituents;
  • L 2 can be selected from optionally fluoro-substituted divalent C 1 -C 3 alkylene moieties;
  • E 4 -E 7 can be independently selected from CH, CR 3 and N, providing at least one of E 4 -E 7 is N, and where R 3 can be selected from methyl and halo substituents.
  • L 1 can be selected from (CH 2 ) n moieties, where n can be an integer selected from 1-3, CH(R 4 )CH(R 5 )CH(R 6 ) moieties where each of R 4 -R 6 can be independently selected from H and fluoro substituents, and moieties where R 4 and R 5 can together and R 5 and R 6 can together form methylene substituents and cyclopropyl moieties.
  • L 2 can be selected from (CH 2 ) m and CH(R 7 )CH(R 8 ) moieties, where m can be an integer selected from 1-3 and each of R 7 -R 8 can be independently selected from H and fluoro substituents.
  • E 5 can be N.
  • the present invention can also be directed to compounds of a formula
  • L 1 and E 4 -E 7 can be as discussed above or illustrated elsewhere herein; and X can be selected, without limitation, from fluoro, chloro, and cyano substituents.
  • L 1 can be selected from optionally-substituted divalent C 1 -C 4 alkylene moieties, where said substituents can be selected from halo, alkyl and divalent methylene substituents; and E 4 -E 7 can be independently selected from CH, CR 3 and N, providing at least one of E 4 -E 7 is N, and where R 3 can be selected from methyl and halo substituents.
  • E 5 can be N.
  • E 4 and E 6 can be independently selected from CH and CR 3 moieties, where each R 3 can be independently selected from methyl and chloro substituents.
  • any stereocenter can be (S) or (R) with respect to any other stereocenter(s).
  • various compounds can be present as an acid salt, either partially or fully protonated.
  • the counterion(s) can be a conjugate base of a protic acid.
  • the present invention can also be directed to a method inhibiting, modulating or otherwise affecting a nitric oxide synthase.
  • a method can comprise providing a compound of this invention, whether or not part of a pharmaceutical composition, and administering an effective amount of such a compound and contacting a nitric oxide synthase therewith, such compounds including but not limited to those illustrated by the following examples, referenced figures and/or accompanying synthetic schemes.
  • such contact can induce, promote or otherwise provide coordination of such a compound with hemoglobin iron in an active site of such a synthase.
  • such a compound and/or combination thereof can be present in an amount at least partially sufficient to selectively inhibit neuronal nitric oxide synthase over inducible and endothelial isoforms.
  • FIG. 1 Compound ( ⁇ )-1 (prior art) is a highly potent and selective nNOS inhibitor; however, it possess multiple charges.
  • compound 7 is a highly potent and selective nNOS inhibitor, that showed good cellular permeability and low efflux ratio, in accordance with certain non-limiting embodiments of this invention.
  • FIG. 3 Schematic illustration of X-ray crystallographic binding mode of compound 7 in the oxygenase domain of nNOS (left) and eNOS (right). Polar interactions are shown by dashed lines.
  • FIG. 4 Modifications on compound 7 can be employed to improve n/i selectivity, minimize cytochrome P (CYP) inhibition, and improve human nNOS potency, respectively, such compounds also in accordance with the present invention.
  • CYP cytochrome P
  • FIGS. 5 and 6 Various other compounds of this invention, in accordance with one or more non-limiting embodiments thereof.
  • arginine mimetics As previously mentioned, many of the highly potent and selective inhibitors of nNOS developed so far are arginine mimetics. As an example, compound 1 showed low nanomolar potency against rat nNOS and >800-fold selectivity over eNOS ( FIG. 1 ). However, increased polar surface area, multiple charges, and >7-8 rotatable bonds adversely affect blood-brain barrier permeability. These drawbacks limit their further development as therapeutic candidates.
  • the imidazole ring is perpendicular over the porphyrin plane with 2.1 ⁇ distance from the central Fe.
  • the propyl linker between the secondary amine group and the aromatic ring enables the 3-fluorophenyl ring to fit in the hydrophobic pocket lined by residues Met336, Leu337, and Tyr706 with electrostatic interactions between the ring and pocket residues.
  • analysis of the crystal structure of 7 bound to eNOS showed that although the orientation of it up to the secondary amine is similar as in nNOS, beyond that the linker is disoriented, and the phenyl ring is pushed out of the pocket. This unstable orientation may account for the poor potency of 7 for eNOS.
  • Compound 7 was promiscuous to some of the liver microsomal cytochrome P450 (P450) enzymes at 10 ⁇ M concentration. This promiscuity is speculated to arise from the 2-imidazolyl fragment in 7, since imidazole is a known heme-Fe coordinating ligand and therefore at 10 ⁇ M concentration, it can bind in the active site of the P450 enzymes. Therefore, determining an IC 50 value to judge its potency towards the cytochrome P (CYP) enzymes, and modification of the 2-imidazolyl fragment of 7 to alleviate its binding to CYPs was considered.
  • P450 liver microsomal cytochrome P450
  • Hemoglobin capture assay performed to determine IC 50 values of the inhibitors, thereafter using the Cheng-Prusoff equation to determine the K i was performed on compounds 25-31 (Table 1).
  • Replacing the 3-F with a 3-Cl did not alter much in the potency or selectivity, however with the cyclopropyl ring ⁇ —to the secondary amine showed an improved selectivity over eNOS and iNOS, without much change in potency.
  • amine starting materials can be prepared via the synthetic techniques outlined in Scheme 4 or straightforward variations thereof.
  • Schemes 1-3 reductive amination of a pyrimidinyl aldehyde or Michael addition to a vinyl pyrimidine with such an amine can provide a substituted pyrimidine core.
  • Azole incorporation affords, for example, a target imidazolyl-pyrimidine scaffold.
  • compositions suitable for such contact or administration can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions.
  • compositions can be, in conjunction with the various methods described herein, for administration or contact with a cellular medium, bacterium and/or a nitric oxide synthase expressed or otherwise present therein.
  • “contacting” means that a nitric oxide synthase and one or more inhibitor compounds are brought together for purpose of binding and/or complexing such an inhibitor compound to the enzyme. Amounts of a compound effective to inhibit a nitric oxide synthase may be determined empirically, and making such determinations is within the skill in the art. Modulation, inhibition or otherwise affecting nitric oxide synthase activity includes both reduction and/or mitigation, as well as elimination of NOS activity and/or nitric oxide production.
  • dosage amount will vary with the activity of a particular inhibitor compound, disease state, route of administration, duration of treatment, and like factors well-known in the medical and pharmaceutical arts.
  • a suitable dose will be an amount which is the lowest dose effective to produce a therapeutic or prophylactic effect.
  • an effective dose of such a compound, pharmaceutically-acceptable salt thereof, or related composition may be administered in two or more sub-doses, administered separately over an appropriate period of time.
  • Methods of preparing pharmaceutical formulations or compositions include the step of bringing an inhibitor compound into association with a carrier and, optionally, one or more additional adjuvants or ingredients.
  • a carrier for example, a pharmaceutically acceptable carrier
  • additional adjuvants or ingredients for example, standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
  • the present invention provides for use of one or more nitric oxide synthase inhibitor compounds for the manufacture of a medicament for therapeutic use in the treatment of various disease states, in particular neurodegenerative diseases.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US14/798,307 2014-07-11 2015-07-13 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase Expired - Fee Related US9701661B2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US14/798,307 US9701661B2 (en) 2014-07-11 2015-07-13 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
US15/602,833 US9878996B2 (en) 2014-07-11 2017-05-23 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462023746P 2014-07-11 2014-07-11
US14/798,307 US9701661B2 (en) 2014-07-11 2015-07-13 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/602,833 Division US9878996B2 (en) 2014-07-11 2017-05-23 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

Publications (2)

Publication Number Publication Date
US20160009690A1 US20160009690A1 (en) 2016-01-14
US9701661B2 true US9701661B2 (en) 2017-07-11

Family

ID=55065107

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/798,307 Expired - Fee Related US9701661B2 (en) 2014-07-11 2015-07-13 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
US15/602,833 Active US9878996B2 (en) 2014-07-11 2017-05-23 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

Family Applications After (1)

Application Number Title Priority Date Filing Date
US15/602,833 Active US9878996B2 (en) 2014-07-11 2017-05-23 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

Country Status (3)

Country Link
US (2) US9701661B2 (fr)
EP (1) EP3166938A4 (fr)
WO (1) WO2016007966A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11439632B2 (en) 2018-12-05 2022-09-13 Northwestern University Use of neuronal nitric oxide synthase inhibitors for immunotherapy in melanoma patients
US12213973B2 (en) 2021-10-18 2025-02-04 Northwestern University Bacterial nitric oxide synthase inhibitors
US12240815B2 (en) 2020-02-24 2025-03-04 Northwestern University Potent and selective human neuronal nitric oxide synthase inhibitors

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2694484T3 (pl) * 2011-04-08 2019-02-28 Janssen Sciences Ireland Uc Pochodne pirymidyny do leczenia zakażeń wirusowych
PL2776439T3 (pl) 2011-11-09 2018-12-31 Janssen Sciences Ireland Uc Pochodne puryny do leczenia zakażeń wirusowych
EP2872515B1 (fr) 2012-07-13 2016-06-08 Janssen Sciences Ireland UC Purines macrocycliques pour le traitement des infections virales
AU2013328732B2 (en) 2012-10-10 2017-08-31 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
MY171115A (en) 2012-11-16 2019-09-26 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino-quinazoline derivatives for the treatment of viral infections
EA035174B1 (ru) 2013-02-21 2020-05-12 Янссен Сайенсиз Айрлэнд Юси Производные 2-аминопиримидина в качестве модуляторов толл-подобных рецепторов tlr7 и/или tlr8
PT2978429T (pt) 2013-03-29 2017-05-24 Janssen Sciences Ireland Uc Deaza-purinonas macrocíclicas para o tratamento de infeções virais
UA117586C2 (uk) 2013-05-24 2018-08-27 ЯНССЕН САЙЄНСІЗ АЙРЛЕНД ЮСі Похідні піридину для лікування вірусних інфекцій та інших захворювань
EA034893B1 (ru) 2013-06-27 2020-04-02 Янссен Сайенсиз Айрлэнд Юси Производные пирроло[3,2-d]пиримидина для лечения вирусных инфекций и других заболеваний
DK3404031T3 (da) 2013-07-30 2020-12-14 Janssen Sciences Ireland Unlimited Co Thieno[3,2-d]pyrimidinderivater til behandling af virusinfektioner
SG11201702041PA (en) * 2015-07-06 2017-04-27 Gilead Sciences Inc Cot modulators and methods of use thereof
AU2017289418B2 (en) 2016-07-01 2021-06-03 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
WO2018060317A1 (fr) 2016-09-29 2018-04-05 Janssen Sciences Ireland Uc Promédicaments de pyrimidine pour le traitement d'infections virales et d'autres maladies
TW201945003A (zh) 2018-03-01 2019-12-01 愛爾蘭商健生科學愛爾蘭無限公司 ２，４－二胺基喹唑啉衍生物及其醫學用途
TW202235416A (zh) 2019-06-14 2022-09-16 美商基利科學股份有限公司 Cot 調節劑及其使用方法
WO2021202224A1 (fr) 2020-03-30 2021-10-07 Gilead Sciences, Inc. Formes solides de (s)-6-(((1-(bicyclo [1.1.1] pentan-1-yl) -1h-1,2,3-triazol-4-yl) 2-méthyl-1-oxo-1,2-dihydroisoquinolin-5-yl) méthyl))) amino) 8-chloro-(néopentylamino) quinoline-3-carb onitrile un composé inhibiteur de cot
AU2021245924B2 (en) 2020-04-02 2024-02-29 Gilead Sciences, Inc. Process for preparing a Cot inhibitor compound

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060116515A1 (en) 2004-12-01 2006-06-01 Kalypsys, Inc. Inducible nitric oxide synthase dimerization inhibitors
US20080108814A1 (en) 2003-09-08 2008-05-08 Silverman Richard B Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
US7470790B2 (en) 2003-09-08 2008-12-30 Northwestern University Heteroaromatic selective inhibitors of neuronal nitric oxide synthase
WO2010057101A2 (fr) 2008-11-17 2010-05-20 Schering Corporation Composés utiles en tant qu’inhibiteurs de vih
WO2012139043A2 (fr) 2011-04-06 2012-10-11 Northwestern University Inhibiteurs sélectifs de l'oxyde nitrique synthase neuronal

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432947B1 (en) * 1997-02-19 2002-08-13 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
WO2004019986A1 (fr) * 2002-08-29 2004-03-11 Schering Aktiengesellschaft Methodes permettant de traiter le syndrome de detresse respiratoire aigue

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080108814A1 (en) 2003-09-08 2008-05-08 Silverman Richard B Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
US7470790B2 (en) 2003-09-08 2008-12-30 Northwestern University Heteroaromatic selective inhibitors of neuronal nitric oxide synthase
US20060116515A1 (en) 2004-12-01 2006-06-01 Kalypsys, Inc. Inducible nitric oxide synthase dimerization inhibitors
WO2010057101A2 (fr) 2008-11-17 2010-05-20 Schering Corporation Composés utiles en tant qu’inhibiteurs de vih
WO2012139043A2 (fr) 2011-04-06 2012-10-11 Northwestern University Inhibiteurs sélectifs de l'oxyde nitrique synthase neuronal

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
International Preliminary Report on Patentability for PCT/US2015/040216 dated Jan. 26, 2017.
International Search Report and Written Opinion for PCT/US2015/040216 dated Jun. 22, 2016, 15 pages.
Mukherjee et al., Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase, Journal of Medicinal Chemistry, vol. 58, No. 3, pp. 1067-1088 (published Dec. 9, 2014). *
Mukherjee, P. et al., "Novel 2, 4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase", Journal of medicinal chemistry, Dec. 9, 2014, vol. 58, No. 3, pp. 1067-1088.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11439632B2 (en) 2018-12-05 2022-09-13 Northwestern University Use of neuronal nitric oxide synthase inhibitors for immunotherapy in melanoma patients
US12083113B2 (en) 2018-12-05 2024-09-10 Northwestern University Use of neuronal nitric oxide synthase inhibitors for immunotherapy in melanoma patients
US12240815B2 (en) 2020-02-24 2025-03-04 Northwestern University Potent and selective human neuronal nitric oxide synthase inhibitors
US12213973B2 (en) 2021-10-18 2025-02-04 Northwestern University Bacterial nitric oxide synthase inhibitors

Also Published As

Publication number Publication date
US9878996B2 (en) 2018-01-30
US20170260165A1 (en) 2017-09-14
EP3166938A2 (fr) 2017-05-17
WO2016007966A3 (fr) 2016-08-11
WO2016007966A2 (fr) 2016-01-14
US20160009690A1 (en) 2016-01-14
EP3166938A4 (fr) 2018-01-17

Similar Documents

Publication Publication Date Title
US9701661B2 (en) 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
US9133144B2 (en) Process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine
US8557552B2 (en) Selective neuronal nitric oxide synthase inhibitors
HK1200052A1 (en) Substituted (e)-n'-(1-phenylethylidene) benzohydrazide analogs as histone demethylase inhiitors
US9951014B2 (en) Mammalian and bacterial nitric oxide synthase inhibitors
Skepper et al. Topoisomerase inhibitors addressing fluoroquinolone resistance in Gram-negative bacteria
US20200331910A1 (en) Mammalian and Bacterial Nitric Oxide Synthase Inhibitors
US10167260B2 (en) 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
US10894096B2 (en) 3,6,9, 15-tetraaza-bicyclo [9.3.1]pentadeca-1(14), 11(15), 12-triene based compounds and their application as ligands of essential metal ion based MRI and 52MN based PET contrast agents
CA2866080A1 (fr) Composes actives par dro en tant que therapies anti-cancer selectives
US9777022B2 (en) Process for the preparation of macrocyclic polyazacarboxylate ligands and chelates
Vasu et al. 2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors
US11034720B2 (en) Thiol-yne based peptide stapling and uses thereof
US9765055B2 (en) Intramolecular hydrogen-bonded nitric oxide synthase inhibitors
Chaves et al. Alkylaryl-amino derivatives of 3-hydroxy-4-pyridinones as aluminium chelating agents with potential clinical application
AU2010268666A1 (en) Fluorinated derivatives of 3-Hydroxypyridin-4-ones
KR20210134306A (ko) 아크릴-함유 핵 수출 조절제들 및 이들의 용도들
US9861626B2 (en) Anti-malarial agent
Sargeson et al. Dependence of the properties of cobalt (III) cage complex as a function of the derivatization of amine substituents
US20190054074A1 (en) Anti-malarial agent
WO2025091117A1 (fr) Composés modulant la fonction physiologique et l'homéostasie
Rossdeutcher Jr Examining the Supramolecular Chemistry of Aromatic Oligoamides: Anion Recognition and Template-Assisted Reactions
US20240182457A1 (en) Oxadiazole-substituted spirocyclic compound and application thereof
US20240002365A1 (en) Pyridazine and 1,2,4-triazine derivatives as fgfr kinase inhibitors
WO2023218251A1 (fr) Nouveaux analogues du néfazodone enrichis en deutérium et leur procédé de préparation

Legal Events

Date Code Title Description
AS Assignment

Owner name: NORTHWESTERN UNIVERSITY, ILLINOIS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SILVERMAN, RICHARD B.;MUKHERJEE, PARAMITA;NGUYEN, HIEN M.;SIGNING DATES FROM 20151009 TO 20151024;REEL/FRAME:036982/0334

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20250711